Abstract
Recently, the discovery of biological and clinical properties of mutated isoforms 1 and 2 mutations of isocitrate dehydrogenases (IDH) 1 and 2, affecting approximately 20% of patients with acute myeloid leukemia (AML), lead to the development of an individualized treatment strategy. Promoting differentiation and maturation of the malignant clone targeting IDH is an emerging strategy to promote clinical responses in AML. Phase I/II trials have shown evidence of safety, tolerability, and encouraging evidence of efficacy of two small molecule inhibitors targeting IDH2 and IDH1 gene mutations, respectively enasidenib and ivosidenib. In this review, the contribution of IDH1/IDH2 mutations in leukemogenesis and progress of targeted therapeutics in AML will be highlighted.
Highlights
INTRODUCTIONIn the last ten years, advances in deciphering genomic landscape have increasingly contributed to the refinement of prognostication in acute myeloid leukemia (AML), incorporating the mutational status of some genes [1,2,3,4] in the WHO classification of AML
In the last ten years, advances in deciphering genomic landscape have increasingly contributed to the refinement of prognostication in acute myeloid leukemia (AML), incorporating the mutational status of some genes [1,2,3,4] in the WHO classification of AML.The current (2017) European Leukemia Net (ELN) classification recommends the stratification of newly-diagnosed AML based on the mutational status of five genes NPM1, CEBPA, FMSlike tyrosine kinase 3 (FLT3), ASXL1, TP53, and RUNX1 [2]
With median follow-up of 8.3 months for 174 adults with isocitrate dehydrogenases isoform 1 (IDH1)-mutated relapsed/refractory (R/R) AML treated with 500 mg ivosidenib daily, the complete remission (CR) + CR with partial hematologic recovery (CRh) rate was 33% [95% confidence interval (CI), 26-40], median duration of response was 8.2 months, and conversion from transfusion dependence (TD) to transfusion independence (TI) occurred in 37% of patients [38]
Summary
In the last ten years, advances in deciphering genomic landscape have increasingly contributed to the refinement of prognostication in acute myeloid leukemia (AML), incorporating the mutational status of some genes [1,2,3,4] in the WHO classification of AML. IDH1/IDH2 mutations play a double role in leukemogenesis: first, mutants induce alterations in the pattern of histone modifications and aberrant DNA methylation, with consequent accumulation of epigenetic aberrancies, associated with reduced TET2 activity [26]; second, mutants can rewire metabolism of AML blasts [25], with sustained inhibition of the activity of cytochrome c oxidase (COX) in the mitochondrial electron transport chain [20] and the glutamine addiction of AML cells for survival [32]. In a human IDH1-mutated tumor xenograft model it showed potent activity in lowering tumor levels of R-2-HG, good pharmacokinetics properties and was well tolerated [37]
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